Lower alkoxytetrahydropyranyl ethers of estrogenic steroids



'ethyl,propyl, and the like. a lower alkenyl group, such United StatesPatent ABSTRACT OF THE DISCLOSURE The 4 (lower) alkoxytetrahydropyran4'-yl ethers of estrogen steroids have high oral activities.

This invention relates to novel and useful 4-(lower)alkoxytetrahydropyran-4'-yl ethers of estrogen steroids, the steroidnucleus thus bearing a new group represented by the formula:

0- o OR wherein R is hydrogen, methyl, methoxy, hydroxyl or conventionalhydrolyzable esters thereof; or X;

R is hydrogen or methyl; and when Z is a single bond, R can be alpha orbeta oriented;

R is hydrogen, hydroxy or conventional hydrolyzable esters thereof (e.g.lower acyloxy or lower cycloacyloxy groups) when Z is a single bond andis hydrogen when Z is a double bond;

R is hydrogen, a lower alkyl group, such as methyl,

as vinyl and the like, or a lower alkynyl (including halo ice loweralkynyl with a halogen, such as fluoro, chloro or bromo), such asethynyl, fluoroethynyl, chloroethynyl,

bromoethynyl, propynyl, trifluoropropynyl, butynyl, hexynyl, and thelike, or

R is methyl or ethyl;

X is a 4' (lower)alkoxytetrahydropyran 4' yloxy p;

X and X eachis hydrogen, hydroxy or conventional hydrolyzable estersthereof, lower alkoxy, lower cycloalkoxy, lower cycloalkenyloxy,tetrahydropyran-2'-yloxy, or X; or X and R together can be keto; and atleast one of X and X is X;

Z is a single or double bond.

The preferred estranes are estra-l,3,5(l0)-trienes having ether groupsat the C3, C17 and C3, 17 positions of the steroidal nucleus. The termestrogen steroids is used herein as denoting estranes having an aromaticA ring, with or without additional unsaturation such as double bondsbetween the C7 and C8 positions of the nucleus.

The terms (lower-alkyl and derivations thereof appearing in the abovedefinitions and elsewhere in the instant specification denote alkylgroups containing from 1 to 6 carbon atoms, inclusive, such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, amyl, hexyl,and the like.

The term conventional hydrolyzable ester as used herein denotes thosehydrolyzable ester groups conventionally employed in the steroid art,preferably those derived from hydrocarbon carboxylic acids or phosphoricacids and their salts. The term hydrocarbon carboxylic acid defines bothsubstituted and unsubstituted hydrocarbon carboxylic acids. These acidscan be completely saturated or possess varying degrees of unsaturation(including aromatic), can be of straight chain, branched chain, orcyclic structure, and preferably contain from 1 to 12 carbon atoms. Inaddition, they can'be substi tuted by functional groups, for example,hydroxy, alkoxy containing up to six carbon atoms, acyloxy containing upto 12 carbon atoms, nitro, amino, halogeno, and the like, attached tothe hydrocarbon backbone chain. Typical conventional hydrolyzable estersthus included within the scope of the term and the instant invention areacetate, propionate, butyrate, valerate, caproate, enanthate, caprylate,pelargonate, acrylate, undecanoate, phenoxyacetate, benzoate,phenylacetate, diphenylacetate, diethylacetate, trimethylacetate,t-butylacetate, trimethylhexanoate, methylneopentylacetate,cyclohexylacetate, cyclopentylpropionate, adamantoate, glycolate,methoxyacetate, hemisuccinate, hemiadipate,hemi-,8,;9-dimethylglutarate, acetoxyacetate, 2 chloro 4 nitrobenzoate,aminoacetate, diethylaminoacetate, piperidinoacetate, B-chloropropionate, trichloroacetate, fi-chlorobutyrate, dihydrogenphosphate, dibenzyl phosphate, benzyl hydrogen phosphate, sodium benzylphosphate, cyelohexylammonium benzyl phosphate, sodium phenyl phosphate,so-

dium ethyl phosphate, di-p-nitrobenzyl phosphate, sodium o-methoxyphenylphosphate, cyclohexylammonium p-cyanobenzyl phosphate, sodium phenacylphosphate, benzyl o-carbomethoxyphenyl phosphate, and the like.

By the term aryl is included aryl, aralkyl, and alkaryl groups, such asphenyl, p-chlorophenyl, p-methoxyphenyl, benzyl, phenethyl, tolyl,ethylphenyl, and the like. The wavy line (I) designates and includesboth the alpha and beta configurations.

The novel 4'-(lower)alkoxytetrahydropyran-4'-yloxy ethers of thisinvention have high oral anti-fertility and estrogenic activity. Thesecompounds can be used paren-- terally in the same manner and dosage asestradiol and when administered orally are used in the same manner asethynylestradiol. The compounds of this invention can be administered inany of the number 011 conventional pharmaceutical forms, andparticularly in ones suited for oral administration, e.g. in solid form,such as in pills, powders, capsules, tablets, or the like, or in liquidform, such as syrups, emulsions, suspensions, and the like.

The preferred compounds of this invention are 17,8-(4'-loweralkoxytetrahydropyran-4'-yl) ethers of esterogenic steroids andparticularly the ethers of secondary l7/3-hydroxy groups, for example,the 17B-(4'-methoxytetrahydropyran-4'-yl) ethers of natural esterogeniccompounds, such as estradiol. Prior to this invention, one of the mosteffective estrogenic agents was estradiol, the natural hormone, butbecause the agent has a very lower oral activity, its use by other thanparenteral routes was impractical. Previously known orally activeesterogenic agents are forms of compounds having structures completelydilferent from estradiol (e.g. ethynylestradiol) and do not provide anatural hormone, such as estradiol, to the body. In contrast, the orallyactivel7q8-(4'-methoxytetrahydropyran-4'-yloxy)estra-1,3,5(10)-trien-3-ol is aform of the natural hormone estradiol and introduces estradiol into thebody when taken orally.

In anti-fertility rat assays by the procedure described by Kincl, F. A.and Dorfman, R. 1., Journal of Reproduction and Fertility, 10, 105(1965) (with the modification of using sesame oil rather than an aqueousvehicle) a daily oral dose of less than 6.2 ug. ofl7/3-(4'rnethoxytetrahydropyran-4-yloxy)estra-l,3,5(10)-trien-3 01provides 100% inhibition; an oral dose of at least from 200- 400 g. ofestradiol is required to provide the same effect, demonstrating the fargreater efiiciency of 178-(4-methoxytetrahydropyran-4'-yloxy)estra-1,3,5(lO)-trien-3-ol as anorally active source of estradiol.

vEstrogenic assays by the procedure described by Bertman, R. I. andDorfman, A. 8., Endocrinology, 55, 65 (1964) (with the modification ofusing corn oil rather than an aqueous vehicle and conducting treatmentfor three rather than four days) show the following oral activities of17/3-(4'-methoxytetrahydropyran-4'-yloxy) estra-l,3,5(l)-trien-3-ol incomparison to estradiol.

Total dose,

This data shows that l7p-(4'-methgxytetrahydropyran-4-yl0xy)estra-l,3,5(l0)-trien-3-ol is about 500% more elfective thanestradiol as an oral estrogen. The oral antifertility activity of17/3-(4'-methoxytetrahydropyran-4'- yloxy) estra-l,3,5 (10)-trien-3-olis even more remarkable, the oral effectiveness being at least 32 timesthe oral effectiveness of estradiol.

The novel steroidal 4-(lower)alkoxytetrahydropyran- 4-yl ethers of thisinvention are prepared by reacting the steroid nucleus having a reactivehydroxyl group at one or more of the 3 and 17,8 positions (dependingupon the particular steroid nucleus) with. an excess of a 4'-(lower)alkoxy-5,6-dihydro-2H-pyran. Free hydroxyl-containing parent compoundswhich are stable under acidic conditions can be reacted undersubstantially anhydrous conditions with an excess of the alkoxydihydropyran in the presence of a small amount of an acidic catalyst,for example, hydrogen chloride, p-toluenesulfonic acid, borontrifluoride etherate, and the like, either alone or together with aninert, organic solvent, such as benzene, diethyl ether, methylenechloride or the like, at a temperature of from 0 C. to about 50 C., andpreferably at room temperature (about 25 C.) for from about one to about72 hours. When the free hydroxyl-containing parent compound is unstableunder acidic conditions, such as allylic hydroxy steroids andestra-l,3,5( l0),7-tetraenes, the reaction is preferably carried out inthe presence of a sulfonyl halide rather than one of the above acidiccatalysts. For this alternative reaction, any stable sulfonyl halide maybe used as the catalyst, especially p-toluenesulfonyl chloride, benzenesulfonyl chloride, p-nitrobenzene sulfonyl chloride, and the like. Thereaction is carried out using a large excess of the dihydropyran suchas, for example, from about ten to 25 parts (molar ratios or parts byweight or volume) either alone or in the presence of a co-solvent, suchas benzene, dioxane, diethyl ether, methylene chloride, and the like, inthe presence of a catalytic amount of the sulfonyl halide such as, forexample, from about 0.001 to 0.1 mole equivalents of sulfonyl halide permole equivalent of dihydropyran. The alkoxytetrahydropyranyl ethersteroid is then isolated in a conventional manner. For example, afterthe reaction is complete, the reaction mixture is treated with a smallamount of pyridine and then poured into a dilute 10% aqueous sodiumbicarbonate solution with stirring, and the product is isolated byextraction with an organic solvent immiscible with water, for example,diethyl ether, methylene chloride, hexane, and the like. The organicextract is concentrated by removing the organic solvent -under reducedpressure at a temperature of less than 40 C. The ether product may bepurified by crystallization or by chromatography on neutral alumina, forexample.

The 4'-(lower) alkoxy-5,-6'-dihydro-2H-pyran reactants used to form theethers of this invention can be prepared by well-known methods. Forexample, tetrahydro-4-pyrone can be reacted with a primary or secondarylower alkanol under acidic conditions to form the intermediate, 4,4 di(lower) alkoxytetrahydropyran, which upon distillation with an acid suchas toluenesulfonic acid or mesitylenesulbfonic acid, yields the4'-(lower) alkoxy-S(,5'-dihydro-2Hpyran product. Such a method isdescribed by Reese et al., J. Am. Chem. Soc. 89, 3367 (1967). The loweralkanol is preferably methanol but it can be other lower alcohols, suchas ethanol, propane], ispropanol, butanol, isobutanol, pentanol, arnylalcohol, hexanol, and the like, to form the corresponding pyrans suchas, for example, 4'-methoxy-5',6'-dihydro-2H-pyran,4'-ethoxy-5',6-hydro-2H-pyran, etc.

The novel estrogen steroid ethers of Formula I can be prepared byprocesses which can be illustrated schematiq cally as by the flow chartin C015. 5 and 6.

In the above formulas, R' is hydrogen, methyl or a conventionalhydrolyzable ester group; R;, is hydrogen or a conventional hydrolyzableester group if Z is a single bond and is hydrogen if Z is a double bond;and R R R R R X and Z have the sam meaning as set forth hereinabove forFormula I. R" is an alkyl or cycloalkyl group, preferably methyl orcyclopentyl; R is an acyl group having from 1 to 12 carbons such asacetyl or a lower alkyl or lower cycloalkyl group such as methyl orcyclopentyl; and R is hydroxy or a conventional hydrolyzable esterthereof.

In carrying out the above illustrated process, to form the ether at C3(Formula VI), the compounds of Formula IV are reacted with a4'-alkoxy-5',6'-dihydro-2H- pyran in the presence of an acidic catalystto form the 3-(4-alkoxytetrahydropyranyl) ethers of Formula V.Protecting groups can then be removed from C-l or C-16ahydroxy groups,if desired. This 17-ketone can then be converted to the corresponding17a-unsubstituted-17flhydroxy derivative (VI: R =H and Rg=hydroxy) or tothe corresponding 17a-(l0W61' alkyl, lower alkenyl, or loweralkynyl-l7fl-hydroxy derivative (1V: R =lower alkyl, lower alkenyl, orlower alkynyl and R =hydroXy) by conventional methods. When desired,selective esterification or etherification can then be used to form therespective groups from liberated, reactive hydroxyls by conventionalprocedures.

When the Not-unsubstituted derivatives are desired, the 3 (4-alko-xytetrahydropyran 4 yloxy) l7 one (V) can be dissolved in an inertorganic solvent, for example, a lower alkanol, such as methanol, anether, such as dioxane or tetrahydrofuran, or the like, and reactedunder neutral conditions with a metal hydride, for example, lithiumaluminum hydride, sodium borohydride, and the like, at a temperatureranging from room temperature to reflux temperature for from about oneto 24 hours, thus giving the corresponding 170t-llI1Sl1bStltIlted- 17B01 (VI), e.g. 3 (4' cmethoxytetrahyrdopyran 4'yloxy)-1,3,5(lO)-estratrien-17/3-ol (V-I: R R and R hydrogen; R =methyl;and R =hydr0xy). This is reaction also cleaves acetoxy groups.

When the 17m (lower)alkyl, (lower)alkenyl or -(lower)alknyl derivativesare desired, the 3'-(4'-tetrahydropyran-4-yloxy)-17-one (V) can berefluxed in thiophene-free benzene under substantially anhydrousconditions, with a lower alkyl, lower alkenyl, or lower alkynylmagnesium halide, such as methyl, vinyl, or ethynyl magnesium bromide,or the like, for about three hours or longer, thus giving thecorresponding 17a-(lower alkyl, lower alkenyl, or lower alkynyl)-17;3-ol(VI), e.g. 3-(4- methoxytetrahydropyran 4 yloxy) 17m methyl (-vinyl or-ethynyl)-estra-1,3,5 (10)-trien-17 3-ol (VI: R R and R hydrogen; R=methyl, vinyl, or ethynyl, re-

spectively; R =methyl; and R =hydroxy). This reaction also cleaves estergroups in the molecule.

Similarly, 3-(4' (lower)alkoxytetrahydropyran 4'- yloXy)-17-one (V)dissolved in absolute diethyl ether can be reacted under an inertnitrogen atmosphere with a lower alkyl, alkenyl, or alkynyl lithiumcompound, such as ethyl lithium, vinyl lithium, ethyanyl lithium, or thelike, for 48 hours or longer at room temperature to provide thecorresponding 17a-(lower alkyl, lower alkenyl, or lower alkynyl)-17B-ol(VI). The 3-(4'-tetrahydropyran-4-yloxy)-l7-one can also be dissolved inanhydrous benzene containing potassium t-amylate and reacted under aninert nitrogen atmosphere with gaseous acetylene at room temperature for40 hours or longer to give the corresponding 17u-ethynyl-17B-ol (VI),which can then be hydrogenated in a known manner to give thecorresponding 17a-vinyl or l7a-ethyl derivatives.

When the 17a-n1onohaloalkylnyl-17 8-hydroxy derivatives are desired, a1,2-dihaloethylene, with at least one of the halogens being other thanfluorine (such as lchloro-2-fluoroethylene, l,2-dichloroethylene, or1,2-dibromoethylene) dissolved in anhydrous diethyl ether, is slowlyadmixed at 0 C., under an inert nitrogen atmosphere with a solution ofmethyl lithium in anhydrous diethyl ether (prepared, for example, byadding lithium to methyliodide in anhydrous diethyl ether solution underan inert nitrogen atmosphere at about 10 C.). This mixture is then heldat room temperature, with stirring, for from about 90 minutes to about12 hours, following which the steroid ether (VI), such as3-(4'-methoxytetrahydropyran 4' yloxy)-estra-1,3,5(l)-trien-17-one (V: RR and R -=hydrogen; R :methyl), is slowly added, and this reactionmixture is held at room temperature for from about 12 hours to about 18hours to give the corresponding l7a-haloethynyl-l7fl-ol (VI). When 1-chloro-2-fluoroethylene is used, a 17a-fiuoroethynyl substituent isobtained, 1,2-dichloroethylene gives a 17mchloroethynyl substituent and1,2-dibromoethylene gives a 17u-bromoethynyl substituent.

A l7u-trifluoropropynyl substituent can be introduced by reacting the3-(4-(loWer)alkoxytetrahydropyran-4- yloxy)-l7-one withtrifluoropropynylrnagnesium bromide (prepared by reactingtrifluoromethyl acetylene with ethylmagnesium bromide under standardGrignard conditions) in an inert organic solvent, preferably a mixtureof diethyl ether and tetrahydrofuran or tetrahydropyran, undersubstantially anhydrous conditions at room temperature for from about 16hours to about 24 hours or longer.

A 170t-(2",2"-difiuorocyclopropenyl) group can be introduced by reactingthe 17aethynyl compound, prepared by an above procedure, with sodiumchlorodifluoroacetate, for example, in anhydrous diglyme, at 60 C. underan inert atmosphere for about 80 minutes. Conventional hydrolyzableesters at C4713 can be prepared from the 17B-ols by conventionalprocedures.

Each of the thus obtained 17a-unsubstituted-l7 8-ols and l'la-(IOWGIalkyl, lower alkenyl, or lower alkynyl)- 17fi-ols corresponding toFormula VI, when reacted with an excess of4'-(lower)alkoxydihydro-ZH-pyran in the manner described hereinabovegives the corresponding 3,175 bis(4'-alkoxytetrahydropyran-4'-yloxy)steroid (VIII), for example,3,17fl-bis(4'-methoxytetrahydropyran-4'-yloxy)-l7ot ethynylestra 1,3,510) triene (VIII: R R and R =hydrogen; R =ethynyl; and R =methyl).

Alternatively, estrone or its derivatives (IV) can be first converted tothe corresponding 170L-I1I1Sl1b8tltl1t6dl7/8-hydroxy derivative (VII: R=hydrogen) or to the corresponding 17a-lower alkyl, lower alkenyl, orlower alknyl)-l7 3-hydroxy derivative (VII: R =lower alkyl, loweralkenyl, or lower alkynyl) by the above described conventional methods.

Reactive hydroxy groups, if any, present at positions other than (1-3and C-17fi in the steroid molecule can be protected or converted todesired esters or ethers by selective esterification or etherificationby conventional procedures. For example, these groups can be acylatedwith a molar insufficiency of acetic anhydride to form a mixture ofacetoxy compounds from which the desired free hydroxy compounds can beseparated by conventional chromatography. Back hydrolysis of theacylated compounds can also be used to free the more reactive hydroxylgroups before chromatographic separation to increase the yield ofdesired products. The dihydroxy compound (VII) can then be reacted withan excess of the 4'-(lower)alkoxy-dihydro-ZI-I-pyran in the presence ofsuitable catalyst as above described to form the corre sponding3,l7B-di(4' lower-alkoxytetrahydropyran-4'- yloxy) compounds of FormulaVIII. For example, estra- 1,3,5 ()-trien-3-oll7-one can be refluxed inthiophene free benzene under substantially anhydrous conditions withethynyl magnesium halide to give the corresponding l7a-ethynylestra-1,3,5 (l0)-triene3,l7B-diol; this product when reacted with4-methoxydihydro-2H-pyran, for example, in the presence ofp-toluenesulfonic acid forms 3,17/3-bis(4'-methoxytetrahydropyran 4'yloxy) 170:-

8 ethynylestra-1,3,5(10)-triene (VIII: R R and R =hydrogen; R =ethyny1;and R =methyl).

Alternatively, estrone or its derivatives of Formula IV can first beetherified at position C-3 by conventional techniques. For example,etherification can be accomplished by treating the 3-hydroxy steroidwith sodium hydride and then cyclopentyl bromide in benzene withrefluxing to form the 3-cyclopentoxy derivative or by reacting the3-hydroxy steroid in a potassium hydroxide ethanol solution containingdimethyl sulfate followed by neutralization with acetic acid to form the3-methoxy derivative. The products (IX) can then be converted to thecorresponding 17a-unsubstituted-l7B-hydroxy derivative (X: R =hydrogen)or to the corresponding t- (lower alkyl, lower alkenyl, or loweralkynyl)-17/3-hydroxy derivative (X =1ower alkyl, lower alkenyl, orlower alknyl) by the above described conventional methods.

Alternatively, the 17B-hydroxy compounds of Formula VII can be acylatedto protect free hydroxy groups at C-3 and C-l6 (if the latter arepresent) by conventional techniques with back hydrolysis andchromatographic separation of mixed esters when needed. For example,acylation can be obtained upon treatment with an appropriate acylatingagent, such as acetic or other anhydride in pyr idine to provide thecorresponding acetylated products represented by Formula X.

The 17/3-hydroxy compounds represented by Formula X can then be reactedwith an excess of 4-(lower)alkoxydihydro-ZH-pyran in the presence of anacidic catalyst to form the corresponding l78-(4-loweralkoxytetrahydropyran-4-yloxy) steroids represented by FormulaXI. For example, estra-1,3,5(10)-trien-3-ol-l7-one can be etherified to3 methoxyestra 1,3,5(10) trien 17 one (IX: -R =methyl); reduced withsodium borohydride in aqueous tetrahydrofuran to 3-methoxyestra-1,3,5(10) trien- 17/8-01 (X: R =methyl) and reacted with 4-methoxy-5,6-dihyd.ro-2H-pyran to form 3-methoxy-l78-(4'-methoxytetrahydropyran-4'-yloxy) estra 1,3,5 (l0)-triene (XI).Alternatively, estra-1,3,5(10)-trien-3,l7-diol (VII) can be acylatedwith a molar equivalent of acetic anhydride, forming a mixture of3-acetoxy and 17B-acetoxy compounds. The 3-acetoxy component can beseparated by conventional chromatography on neutral alumina, forexample, and can then be reacted with 4'-ethoxydihydro- ZH-pyran, forexample, in the presence of an acidic catalyst, such as hydrochloricacid to form the corresponding 3 -acetoxy- 17 B-(4'-ethoxytetrahydropyran-4'-ylxoy) -estraestra-1,3,5 lO)-triene (XI).

The ester groups in the compounds of Formulas V, VI, VIII and XI canthen be hydrolyzed by conventional techniques to convert the estergroups(s) to the corresponding hydroxy group(s).

In reacting the C-3, 0-175 and C-3,17B hydroxy compoundsherein-disclosed with 4'-(lower)alkoxy-5',6'-dihydro-2H-pyran by theprocedures described herein to form the4'-(-lower)alkoxytetrahydropyran-4-yl ethers of this invention, a secondseries of ethers, that is, 5','6'-dihydro-'2H-pyran-4'-yl ethers of thestarting materials are also formed. This second series of etherscorrespond to those represented by Formula I wherein X is the 5',6'-dihydro-2H-pyran-4-yloxy group. Hydrocarbon solvents for thereaction medium, higher catalyst concentrations, and longer reactiontimes increase the yield of the 5Z6- dihydro-2H-pyran-4'-yloxycompounds; use of ether or tetrahydrofuran solvents, lower catalystconcentrations, and shorter reaction times increase the yield of the 4-(lower)alkoxytetrahydropyran-4-yloxy compounds. This second series ofcompounds can be separated from the reaction products by conventionalchromatographic techniques.

These 5',-6'-dihydro-2H-pyran-4'-yl ethers have high oral anti-fertilityand estrogenic activity. These compounds can be used parenterally in thesame manner and dosage as estradiol and when administered orally areused in the same manner as ethynylestradiol. They can be administered inany of the number of conventional pharmaceutical forms, and particularlyin ones suited for oral administration, e.g. in solid form, such as inpills, powders, capsules, tablets, or the like, or in the liquid form,such as syrups, emulsions, suspensions, and the like.

Examples ethers are 3- 5 ',6'-dihydro-2H-pyran-4'-yloxy) -estral ,3,5 10trien-17-one,

3-( 5 ,6'-dihydro-2H-pyran-4'-yloXy) -estra-1,3,5 l trien-17-[3-ol,

3- ',6'-dihydro-2H-pyran-4-yloxy 17a-ethynylestra- 1,3,5()-trien-17B-ol,

3- 5',6-dihydro-2H-pyran-4'-yl0xy) -7oz-methyl-17aethynylestra-1,3,510)-trien-l7B-ol,

3- (5 ,6'-dihydro-2H-pyran-4'-yloxy -estra-1,3,5( l0) 7-tetraen-17-one,

3, 17fl-bis 5 ,6-dihydro-2H-pyran-4'-yloxy) -estral,3,5(10)-triene,

1,3-bis (5',6'-dihydro-2H-pyran-4-yloxy) -17a-ethyny1estra-1,3,5(10)-trien-l7/i-ol,

1,3-bis 5 ',6'-dihydro-2H-pyran-4'-yloxy) -17u-ethynyl-17p-acetoxyestra-1,3,5 10 -triene,

17;8-( 5 ,6-dihydro-2H-pyran-4'-yloxy) -estra-1 ,3,5 10 trien-3-ol,

17,3-(5,6'-dihydro-4-yloxy)-18-methylestra-1,3,5( 10)- trien-3-ol,

3-cyclopentoxy-l7fi-(5',6'-dihydro-2H-pyran-4'-yloxy)- estra-1,3,5(70)-triene,

3-cyclopentoxy-17B-(5,6'-dihydro-2H-pyran-4'-yloxy)-18-methylestra-1,3,5 10) -triene,

3-acetoxy-17B-(5,6'-dihydro-2H'pyran-4'-yloxy)-estra- 1,3,5(10)-triene,

3-tetrahydropyran-2'-yloxy-175-(5',6-dihydro-2H- pyran-4-yloxy)-estra-1,3,5( 10) -triene,

3-cyclopentoxy-17u-ethynyl-17,8- (5',6-dihydro-2H pyran-4'-yloxy)-estra-1,3,5 10)-triene,

3 -cyclopentoxy-17a-ethynyl-17p- (5,6'-dihydro-2H-pyran-4-yloxy)-18-methylestra-1,3,5 10)-triene,

1,3-diacetoxy-17a-ethyny1-17fl-(5,6-dihydro-2H-pyran-4-yloxy)-estra-1,3,5(10)-triene,

17a-ethynyl-17fl- (5,6-dihydro-2H-pyran-4'-yloxy) estra-1,3,5 10-triene-3 1 6a-dioi,

175- 5 ',6'-dihydro 2H-pyran-4'-yloxy) -estra- 1,3,5 10 7-tetraen-3-ol,and the like.

The starting materials used in the above illustrated process are knownin the art or can be obtained by methods known in the art.

Referring to Formula IV, l-methyl derivatives of estrone, such as1-methylestra-1,3,5(10)-triene-3-ol-17-one have been disclosed inTetrahedron, 3,. 28 (1958). C-l hydroxy and ester derivatives of estroneand methods for their preparation have been previously described in US.Pat. No. 2,861,086.

Estrone derivatives having C-7a methyl groups, such as 70: methylestra1,3,5( 10) trien 3-ol-17-one, and methods for their preparation havebeen described by Kalvoda et al., Helvetica Chimica Acta., 50, 281(1967).

Estrone derivatives containing hydroxy or ester groups at C-16, such asestra-1,3,5(10)-triene-3,16a-di0l-17-one and the correspondingl6uesters, such as Mot-acetate, and methods for their preparation havebeen described by Leeds et al., Am. Soc. 76, 2943 (1954). Thecorresponding C1 hydroxy substituted compounds, such as estra- 1,3,5l0)-triene-1,3,16a-triol-l7-one and the respective 1,l6oc-acetates, andmethods for their preparation have been described in US. Pat. No.3,024,256. Estrone derivatives containing a l-methyl group incombination with a 16ot-hydroxy or -ester group, such as1-methylestra-1,3,S (10)-triene-3,16u-diol-17one, can be prepared fromthe corresponding l-methyl estrone by the method described of suitable5,6'-dihydro-2H-pyran-4'-yl 10 by Engelfried et al.,Arznelmittelforschung, 11, 25 (1966), page 1518.

Estrone derivatives containing a C-18 methyl group, such as8-methylestra-l,3,5(10)-trien-3-ol-17-one can be prepared by theprocedure described by Smith et al., Experientia, vol. 19, pp. 394396(1953).

These and other starting materials represented by Formula IV can beprepared by total synthesis following the procedure describedhereinafter.

PREPARATION OH3O R2 0 OH s l CHaO Rz In the above equation, the1-vinyl-6-methoxy-1-tetralol and its C3 and C-8 substituted counterpartscan be prepared from the corresponding 6-methoxytetralone and its C-3and C8 substituted derivatives, all of which are known by the proceduredescribed in articles by Ananchenko et al., Dokladii Akad. Nauk SSSR,112, 1067 (1957) and Tetrahedron, 18, 1355 (1962).

The 2-methy1 (or -ethyl) cycIopentane1,3-dione represented by Formula Bis well known and has been previously described by Smith et al., J.Chem. Soc., p. 4472 (1964).

In the above Formulas A, B and C, as well as in formulas appearinghereinafter, R R and R have the meanings described with respect toFormula I hereinabove.

1-vinyl-6-methoxytetralol (112 g.) and Z-ethylcyclopentane-1,3-dione g.)are refluxed for six hours in methanol (275 cc.) containing potassiumhydroxide (0.3 g.). Most of the methanol is evaporated and etherbenzene(800 cc; 1:1) is added. The solution is washed successively with water,5% aqueous sodium hydroxide solution, water and brine, and dried. Theproduct is recrystallized from methanol (180 cc.) to give 2-ethyl-2-(1,2,3,4 tetrahydro 6 methoxynaphth-l-ylidenethyl)-cyclopenta-1,3-dione. Concentrated hydrochloric acid (50 cc.) is addedwith stirring over one minute to the foregoing dione g.) in ethanol (750cc.) at 50. After stirring for five minutes, warm (50 C.) cyclohexane(one liter) is added followed by water (350 cc.), and stirring continuedfor five minutes. The aqueous layer is extracted with cyclohexane andthe combined organic solutions are washed, dried and evaporated. Theresidue is dissolved in hot ethanol (200 cc.) containing cyclohexane (20cc.) and kept at 0 C. for 16 hours. The precipitate is filtered, dried,purified by percolation in cyclohexane-benzene (9:1) through florisil,and recrystallized from ethanol-cyclohexane 10:1) to give the ketone 3methoxy-18-methylestra-1,3,5(10),8,14penten- 17-one. This compound (670g.) in benzene (2.15 1.) containing 2% palladised calcium carbonate (225g.) is shaken with hydrogen until 57.64 1. have been absorbed (112minutes). Filteration and evaporation gives a residue which isrecrystallized from methanol to give a product (561.1 g.) 3 methoxy 18methylestra-1,3,5(10),8,(9)- tetraen-17-one.

The latter compound (16.8. g.) is added in portions with stirring tosodium borohydride (6 g.) in methanol (500 cc.) under reflux. Themixture boils spontaneously. Acetic acid (15 cc.) is added to the cooledsolution, most of the solvent is evaporated, Water is added, and themixture is extracted with ethyl acetate. The product is recrystallizedfrom acetonitrile to give3-methoxy-18-methylestra-1,3,5(10),8-tetraen-17/3-ol (13.8 g.) which isrepresented by Formula C above (Where R and R =hydrogen; R =ethy1).

Following the above procedure except replacing the1-vinyl-6-methoxy-l-tetralol with tetralols substituted at the C-3 andC8 positions, that is, 1-vinyl-3-methyl-6- methoxy 1 tetralol,1-vinyl-3,8-dimethyl-6-methoxy-1- tetralol,1-vinyl-6-methoxy-S-methyl-l-tetralol, 1-vinyl-6, 8 dimethoxy 1 tetraloland 1-vinyl-3-methyl-6,8-dimethoxy-l-tetralol, the corresponding C-1 andC-7 substituted 3-methoxy-18-methylestra-1,3,5(10), 8-tetraen-17fi-olsare obtained, a 3-methoxy-7,18-dimethylestra-1,3,5(10), 8tetraen-175-ol, 1,7,18-trimethyl-3-methoxyestra-1,3,5 (10),8-tetraen-17[i-ol, l,18-dimethyl-3-methoxyestra-l,3,5 (10),8-tetraen-17fl-ol, 1,3-dimethxy-18-methylestra-1,3,5 (10),8tetraen-17/8-ol and 1,3-dimethoxy-7,8-dimethylestra-1,3,5 10),8-tetraen- 175-01.

Similarly, by following the above procedures with each of the named orindicated 1-vinyl-6methoxy-l-tetralols but replacing theZ-ethylcyclopentane-l,3-dione with 2- methylcyclopentane-1,3-dione, thecorresponding l8-unsubstituted estra-1,3,5(10),8-tetraenes are formed,e.g. 3- methoxyestra 1,3,5 (10),8 tetraen-17;3-ol, 3-methoxy-7-methylestra 1,3,5(10),8-tetraen-l7[3-ol, 1,7-dimethyl-3- methoxyestra1,3,5(10),8 tetraen-17fi-ol, 1-methyl-3- methoxyestra1,3,5(10),8-tetraen-17/3-ol, 1,3-dimethoxyestra-1,3,5 10,8-tetraen17/3-ol and 1,3-dimethoxy-7-methylestra- 1,3,5( 10),S-tetraen- 175-01.

In the above formulas, C and D, R R and R represent the same groupsdescribed with respect to Formula I hereinabove.

Lithium (6 g.) is added in portions with stirring toS-methoxy-18-methylestra-1,3,5(10),8-tetraen 17,8 01 (16.8 g.) in liquidammonia (400 cc.) -aniline (150 cc.) -tetrahydrofuran (50 cc.) Afterstirring for two hours, ammonium chloride (50 g.) and then water (600cc.) are added, and the mixture is extracted with ether. The product,3-methoxy-18-methylestra 1,3,5 (10) trien-175-ol, is recrystallized fromhexane. To this compound (50 g.) in acetone (2 l.) containing anhydrousmagnesium sulfate (60 g.) is added 8 N-chromic acid with stirring. Themixture is stirred for five minutes and propan-Z-ol (200 cc.) and sodiumhydrogen carbonate (100 g.) are added. The solids are filtered from themixture and washed with hot chloroform. Evaporation of the combinedfiltrate and washings give a residue which is percolated in etherthrough a column of neutral alumina. Recrystallization of the productfrom methanol gives the ketone 3-methoxy- 18-methylestra-1,3,5(10)-trien17 one represented by Formula D. Following the same procedure butreplacing the 3-methoxy-18-methylestra-1,3,5(10),8-tetraen-17fl-ol withthe corresponding compounds wherein R is methyl or methoxy, R ishydrogen or methyl, and R is methyl or ethyl, the correspondingsubstituted 3-methoxyestra 1,3,5(10)-trien-17-ones are produced, e.g.1,7(a or dimethyl-3-methoxyestra 1,3,5() trien-17-one, 1,7 (a or{3),18-trimethyl-3-methoxyestra 1,3,5 (10)-trien- 17-one,1,3-dimethoxyestra-1,3,5(10)-trien-17-one, 1,3- dimethoxy-7(a or,B)-methylestra-1,3,5(10)-trien-17-one, 1,3dirnethOXy-7(ot or,6),18-dimethylestra-1,3,5(10)-trien OH 0 R I 1 6 i j R1 1 l it CH3O R2CH30 V R2 In Formulas C and E, R R and R represent the same groups as inFormula I.

B-methoxy-l8-methylestra-1,3,5(10),8-tetraen 17 3-01 (1 g.) is mixedwith a benzene-hexane solution (1:1) of 1.15 equivalents of m-chloroperbenzoic acid at 0 C. The reaction mixture is allowed to stand forfive hours at 0 C. and then washed with a sodium bicarbonate solutionand water, dried and evaporated, giving a mixture of 3-methoxy8,9-oxo-18-methylestra-1,3,5(10)-trien-17/3-ol and 3-methoxy 18methylestra-1,3,5(10),9-tetraene-8u, 17fl-diol. The mixture is added toa solution of benzoic acid and chloroform converting the mixture to apure 3-methoxy 18 methylestra-1,3,5(10),9(11)-tetraene- 8u,17B-diol. Thereaction mixture is washed with sodium carbonate solution and water,dried and evaporated.

A solution of the last named compound (2 g.) in meth anol (200 ml.) isadded to a suspension of 5% palladiumon-carbon catalyst (0.5 g.) inmethanol (50 ml.) which has been hydrogenated for 30 minutes, andhydrogenation with agitation is continued until the uptake of hydrogenhas ceased. The catalyst is removed by filtration and the solution isevaporated to yield 3-methoxy-l8-methylestra- 1,3,5(10)-triene-8a,175-diol which is recrystallized from methylenechloride2hexane for further purification. This compound (1 g.) is thenrefluxed with an excess of methanesulfonyl chloride in pyridine untilthe dehydration is complete. Water is added to the reaction mixture andit is extracted with chloroform; the chloroform solution is thenevaporated to dryness. Refiltration of the product in benzene throughfiorisil and recrystallization from methanol yields purified3-rnethoxyestra-1,3,5(10),7-tetraene- 17p-methylsulfonate.

A solution of the last named compound (1 g.) and tetrahydrofuran (50ml.) is added over a 30 minute period to a stirred suspension of lithiumaluminum hydride (1 g.) in anhydrous tetrahydrofuran (50 ml.), and thismixture is heated at reflux for two hours. To the mixture is cautiouslyadded ethyl acetate (5 ml.) and water (2 ml.)- Sodium sulfate is nextadded and the mixture is filtered; the solid thus collected is washedwith hot ethyl acetate. The combined organic solutions are thenevaporated to dryness and recrystallized from acetonezhexane to yield3-methoxy-18-methylestra-1,3,5 10) ,7-tetraen-17B-ol.

To the Grignard reagent from magnesium (51 mg.) and methyliodide (0.16cc.) in ether (3 cc.) is added this compound, and the mixture is heatedin an oil bath at C. for one and one-half hours. The cooled mixture isthen treated with dilute acetic acid and ether and the latter isextracted thoroughly with 5% potassium hydroxide solution, yielding18-methylestra-l,3,5(10,7-tetraene- 3,17fl-diol.

A solution of the last mentioned compound (1 g.) in xylene (30 ml.) andcyclohexanone (10 ml.) is distilled to remove moisture. A solution ofaluminum isopropoxide (1 g.) in xylene (5 ml.) is added dropwise overfive minutes to the slowly distilling solution, distillation beingcontinued for an additional 45 minutes. The mixture is then cooled anddiluted with water, a mixture of water and the solvents being removed bysteam distillation. The resulting solid is collected by filtrationthrough Celite diatomaceous earth and dried. This solid is extractedwith hot acetone and recystallized from acetone to yield18-methylestra-1,3,5(10),7-tetraen-3-ol-17-one represented by Formula Eabove.

Repeating the above procedure except for replacing the 3-methoxy-l8-methylestra-1,3,5 10) ,8-tetraen-l7B-ol with the correspondingsubstituted compounds wherein R is methyl or methoxy, R7 is hydrogen,a-methyl or B-methyl and R is methyl or ethyl, and adjusting theconcentrations of reactants to compensate for additional reactive groups.(e1g. increasing the concentration of the Grignard reagent to cleaveboth the C-1 and the C3 methoxly groups to the corresponding hydroxygroups), the corresponding substituted estra-1,3,5(10),7-tetraenes areproduced, for example, 1-methylestra-1,3,5(10),7-tetraen-3- ol-17-one,1,7'dimethylestra-i1,3,5 10) ,7 -tetraen-3-ol- 17 one, 1,18dimethylestra 1,3,5(lO),7-tetraen- 3 01-17- one1,7,18-trimethylestra-1,3,5 10) ,7-tetraen-3-ol-17-one, estra-1,3 ,5 10),7-tetraene-1,3-diol-17-one, 7-methylestra- 1,3,5.(10),7-tetraene-1,3-diol-17-one, 18-methylestra-1,3,5 10),7-tetraene-1,3-diol- 17-one, 7,l8-dimethylestra-1,3,5(l),7-tetraene-1,3-diol-17-one and 7,18-dimethylestra- 1,3,5 l0),7-tetraen-3-o1-17-one.

The invention is further illustrated by the following specific butnon-limiting examples.

Example 1 Two milliliters of 4-methoxy-5',6-dihydro-2H-pyran are addedto a solution of 1 g. of estra-l,3,5(10)-trien-3- ol-17-one in 15 m1. ofbenzene. About 1 ml. is removed by distillation to remove moisture and0.4 g. of p-toluenesulfonic acid is added to the cooled solution. Thismixture is allowed to stand at room temperature for four days and isthen washed with aqueous sodium carbonate solution and water, dried andevaporated. The residue is chromatographed on neutral alumina, elutingwith hexane, to yield 3 (4' methoxytetrahydropyran 4' yloxy)-estra-1,3,5.(l0)-trien-17-one which is recrystallized from pentane.

Following the same procedure but replacing the 4'-methoxy-S,6-dihydro-2H-pyran with 4'-ethoxy-5',6'-dihydro-Z-H-pyran,4'-propoxy-5',6-dihydro-2H-pyran, 4'- isopropoxy-S,6'-dil1ydro-2H-pyran,4-butoxy-5',6'-dihydro-2H-pyran, 4'-is0butoxty-5',6'-dihydro-2H-pyran,4'- pentoxy ',6'-dihydro-2H-pyran, 4-amyloxy-5',6-dihydro-ZH-pyran and4'-hexoxy-5,6'-dihydro-2H-pyran, the corresponding 3 (4'loweralkoxytetrahydropyran-4yloxy) ethers are obtained, e.g.3-(4'-ethoxytetrahydropyran- 4-yloxy)-estra 1,3,5(l0) trien-17-one,3-(4-propoxytetrahydropyran 4'-yloxy)-estra-l,3,5(10)-trien-17-one, 3.(4'-butoxytetrahydropyran-4'-yloxy)-estra-1,3,5(10)- trien-17-one and3-(4'-hexoxytetrahydropyran-4'-yloxy)- estra- 1,3,5 )-trien-17-one.

By repeating the above procedures with estra-1,3,5(10)- trienes havinghydrogen, methyl, methoxy or hydrolyzable ester groups at C-1; hydrogenor methyl groups at C7; hydrogen or ester groups at C16; and hydrogen ormethyl groups at C18 yields the corresponding etherified products, e.g.3-(4'-methoxytetrahydropyran-4'-yloxy)- 7a methylestra1,3,5(10)-trien-17-one, 3-.(4'-methoxytetrahydropyran 4'-yloxy) 18methylestra-1,3,5(10)- trien-17-one,1-methyl-3-(4'-methoxytetrahydropyran-4'- yloxy) -estra-1,3,5 10)-trien-17-one, 3- (4'-methoxy-tetrahydropyran 4'yloxy)-estra-1,3,5.(10)-trien-16a-ol-17- one, and the like.

Repeating the above procedure except replacing estra- 1,3,5(10)-trien-3-ol-17-one with extra-1,3,5 10)-trime- 1,3-diol-l7-one andusing 4 ml. of 4-methoxy-5,6'-dihydro-2H-pyran yields1,3-bis(4'-methoxytetrahydropyran- 4-yloxty) -estra-1,3,5(10)-trien-17-one.

Example 2 Two milliliters of 4'-methoxy-5',6'-dihydro-2H-pyran are addedto a solution of 1 g. of estra-1,3,5.(10),7-tetraen- 3-ol-17-one in 15ml. of benzene. About 1 ml. is removed by distillation to removedmoisture and 0.4 g. of p-toluenesulfonyl chloride is added to the cooledsolution. This mixture is allowed to stand at room temperature for fourdays and is then washed with aqueous sodium carbonate solution andwater, dried and evaporated. The residue is chromatographed on neutralalumina, eluting with hexane, to yield3-(4'-methoxytetrahydropyran-4-y1oxy)- estra-1,3,5(1'0),7-tetraen-17-onewhich is recrystallized from pentane.

Following the same procedure but replacing the 4- methoxy-5',6'-dihydro-2H-pyran with 4'-eth0xy-5',6'-dihydro-2H-pyran,4'-propoqy-5',6'-dihydro-2H-pyran, 4'- isopropoxy 5',6'dihydro-2H-pyran,-4'-butoxy-5',6'-dihydrO-ZH-pyran,4'-isobutoxy-5',6-dihydro-2H-pyran, 4- pentoxy 5',6-dihydro-2H-pyran,4-amyloxy-5',6'-dihydro-2H-pyran and 4-hexoxy-5',6' dihydro-2H-plyran,the corresponding 3 (4' loweralkoxytetrahydropyran-4'-yloxy) ethers areobtained, e.g. 3-(4'-ethoxy-tetrahydropyran-4'-yloxy)-estra 1,3,5(l0),7tetraen 17-one, 3-(4'- propoxytetrahydropyran 4yloxy)-estra-1,3,5(10),7- tetraen 17 one,3-(4-butoxytetrahydropyran-4-yloxy)- estra 1,3,5(10),7-tetraen-17-oneand 3-(4'-hexoxytetrahydropyran-4-yloxy) estra-1,3,5 10),7-tetraen-l7-one.

Products having other substituents at C1, C7, C-16 and C-18 as describedwith respect to Formula V are obtained from the corresponding Formula IVcompounds by this procedure.

Example 3 A solution of 1 g. of 3e(4-methoxytetrahydropyran-4'-yloxy)-estra-1,3,5 (10)-trien-l7-one in 50 ml. of tetrahydrofuran isadded over a 30 minute period to a stirred suspension of 1 g. of lithiumaluminum hydride in 50 ml. of anhydrous tetrahydrofuran and this mixtureis heated at reflux for two hours. To the mixture are cautiously added 5ml. of ethyl acetate and 2 ml. of water. Sodium sulfate is next added,the mixture is filtered and the solid thus collected is washed with hotethyl acetate. The combined organic solutions are then evaporated toyield 3-(4- methoxytetrahydropyran 4'-yloxy)-estra-1,3,5(10)-trien- -01,which may be further purified through recrystallization fromacetonezhexane.

Following the same procedure but replacing the 3-(4'-methoxytetrahydropyran-4' yloxy) estra l,3,5(10)- trien-l7-one with theother estra-l,3,5'(10)-trien-17-one products of Examples 1 and 2 havingat 4' other lower alkoxy groups such as ethoxy, propoxy, butoxy, hexoxy,and the like; having at C1 (R hydrogen, methyl or methoxy; at C7 (R aorfi-methyl when the bond between C6 and C7 is a single bond; Cl6 (R' ishydrogen or an ester group such as acetyloxy group; Cl8 (R is hydrogenor methyl; and the bond between C7 and C-8 is a single or double bondgives the corresponding 17,8-hydroxy products, e.g.3-(4'-methoxytetrahydropyran-4'-yloxy) 7a methylestra-l,3,5(l0) trienl78-ol, 3 -(4' methoxytetrahydropyran-4'-yloxy)46aacetyloxyestra 1,3,5(10trien 17,8-01, 3-(4'-methoxytetrahydropyran 4 yloxy)estra-l,3,5(10,7-tetraen- 17,8-01, etc.

Example 4 A solution of one chemical equivalent of3-(4-methoxytetrahydropyran 4' yloxy) estra l,3,5(l0)-trien 175-01 in 30ml. of benzene is heated to reflux and about 2 ml. removed bydistillation to eliminate moisture. The mixture is cooled to roomtemperature and two chemical equivalents of sodium hydride are added,followed by the dropwise addition of two chemical equivalents ofcyclopentyl bromide in 10 m1. of benzene over a period of 20 minutes.The mixture is allowed to reflux for 20 hours after which time therecipitate of sodium bromide is removed by filtration and the organicphase dried and evaporated to yield 3-(4-methoxytetrahydropyran-4-yloxy) 17,8 cyclopentoxyestra-l,3,5=(10)-triene which is furtherpurified upon recrystallization from pentane. Repeating this procedurewith other products of Examples 1 and 2 yields the corresponding17fi-cyclopentoxy compounds.

A mixture of 3-(4-methoxytetrahydropyran-4-yloxy)-estra-1,3,5(10)-trien-17fi-ol (0.32 g.) and cyclohexanone diethyl ketal(1.0 ml.) is heated at 130 to 140 C. for 30 minutes, then 175 to 180 C.for 15 minutes and finally at 180 to 185 C. for 30 minutes whiledistilling of the volatile ethanol. The reaction product is dissolved inbenzene, purified by chromatography on alumina, and recrystallized froma mixture of ether, methanol, and pyridine to give3=(4'-rnethoxytetrahydropyran-4-y1oxy)- 17,8-cyclohexenyloxyestra-1,3,5(10)-trien. Repeating this procedure with other products of Example 3yields the corresponding l7fl-cyclohexenyloxy compounds.

Example 5 A mixture of 1 g. of 3-(4'-methoxytetrahydropyran-4-yloxy)-estra-l,3,5(10)-trien-l7/3-ol, 4 ml. of pyridine, and 2 ml. ofacetic anhydride is allowed to stand at room temperature for 15 hours.The mixture is then poured into ice water and the solid which forms iscollected by filtration, washed with water, and dried to yield 3-(4'methoxytetrahydropyran 4 yloxy) l7B-acetoxyestra- 1,3,5 (10)-trienewhich may be further purified through recrystallization fromacetone:hexane.

Following the same procedure, esters having hydrogen, methyl or methoxygroups at C1 (R hydrogen or methyl groups at -7 (R hydrogen, methoxy orhydrolyzable esters at 0-1611 (R;,); and hydrogen or methyl group at C18(R are obtained from the corresponding 17fl-hydroxy compounds producedin Example 3.

Example 6 To a solution of 5 g. of 3-(4'-methoxytetrahydropyran-4-yloxy)-este'ra-l,3,5(10)-trien-l7B-ol in 100 ml. of anhydrous benzeneare added 1 g. of p-toluenesulfonic acid and ml. of undecenoicanhydride. The mixture is allowed to stand for 24 hours at roomtemperature and poured with stirring into ice and water. The organicphase is separated, washed with 10% sodium carbonate solution and withwater, dried and evaporated to yield 3-(4-methoxytetrahydropyran 4'yloxy) 175-undecenoyloxyestra-1,3,5(10)-triene which is further purifiedthrough recrystallization from etherzhexane.

Following the same procedure using other acid anhydrides, such asbutanoic anhydride, heptanoic anhydride, etc., the corresponding estershaving two are more carbons in the ester group are formed, e.g.3-(4'-methoxytetrahydropyran 4' yloxy) 17fi-heptanoyloxyestra-1,3,5(l0)-triene, and the like are formed. Similarly,estra-1,3,5(10-triene-17fi-ols having groups at C1, C7, Cl6 and C18 asindicated in Formual VI (products of Examples 3) are converted to thecorresponding 17,8- esters by this procedure.

Example 7 A solution of 1 g. of 3-(4'-methoxytetrahydropyran-4'-yloxy)-estra-1,3,5(10),7-tetraen-17,8ol in 60 ml. of anhydrous ether istreated with 7.5 molar equivalents of ethylmagnesium bromide in etherand, after a few minutes, with 7.5 molar equivalents of acetyl chloride.The mixture is allowed to stand at room temperature for hours, thendiluted with water, and extracted with methylene chloride. The extractsare washed with water to neutrality, dried and evaporated. The residueis chromatographed on neutral alumina, eluting with ether: hexane, toyield 3-(4-methoxytetrahydropyran-4-yloxy)- 1 617B-acetoxyestra-1,3,5'(10),7-tetraene which is recrystallized fromacetoneahexane.

Following the same procedure using other acid chlorides, estra 1,3,5(10)trien 17,8 ols and/0r estral,3,5(l0),7-tetraen-17B-ols having group atC1, C7, Cl6 and C18 as indicated in Formula VI are converted to thecorresponding 175-esters.

Example 8 Following the procedures of Example 1 but replacingestra-1,3,5(10)-trien 3 ol-17-one with 3-(4'-methoxytetrahydropyran 4'yloxy)-estral,3,5(10)-trien-l7/3- ol, 3,17/3-bis(4'methoxytetrahydropyran 4'-yloxy) estra-1,3,5 (10-triene is obtained.

Following the procedures of Example 2 but replacingestra-1,3,5(l0),7-tetraen-3-ol-17-one with 3-(4'-methoxytetrahydropyran4' yloxy) estera-1,3,5( l0),7-tetraen- 175-o1 yields the corresponding3,175-bis(4'-methoxytetrahydropyran-4'-yloxy -estra-1,3 ,5 10),7-tetraene.

Similarly, other 3,175-bis(4'-alkoxytetrahydropyran-4'- yloxy) ethersare obtained from other 4-alkoxy-5,6-dihydro-2H-pyrans. Substitutingother estra-1,3,5(10)-trien- 175-01s andestra-1,3,5(10),7-tetraen-17,8-ols having substituents at C1, C7, C16and C18 as indicated in Formula VI (with reactive hydroxyl groups otherthan at C-3 and C-17,8 being suitably protected) yields thecorresponding substituted 3,17fi-bisethers (compounds of Formula VIII).

Example 9 A solution of 5 g. of 3-(4'-methoxytetrahydropyran-4'-yloxy)-estra-l,3,5(10-trien-l7 one in 250 ml. of thiophene-free benzeneis treated with an equimolar amount of methylmagnesium bromide inanhydrous ether. The mixture is heated at reflux under anhydrousconditions for three hours, cooled and cautiously treated with excessaqueous ammonium chloride solution. This mixture is then extracted withethyl acetate and these extracts are in turn washed with water, driedover sodium sulfate, and evaporated to dryness to yield3-(4-methoxytetrahydropyran 4'yloxy)-17a-methylestra-1,3,5(10)-trien-l7fl-ol which is recrystallizedfrom methylene chloridezhexane.

Repeating the procedure with other lower alkylmagnesium bromides, suchas ethyl magnesium bromide, propylmagnesium bromide, butylmagnesiumbromide, amylmagnesium bromide and hexylmagnesium bromide, yields thecorresponding 17a-ethy1, 17a-propyl, 17a-butyl, 17aamyl and l7oc-h6XY1compounds. Repeating the procedure with other products of Examples 1 and2 yields the corresponding 17a-1OW61 alkyl compounds.

Example 10 Following the procedure of Example 5 but replacing themethylmagnesium bromide with vinylmagnesium bromide yields3-(4-methoxytetrahydropyran-4-yloxy)47avinylestra-l,3,5(10)-trien-17p-ol.Other lower alkenylmagnesium bromides, such as 1'-propenyl, 2'-propenyl,1'-butenyl, 2'-butenyl, and the like, magnesium bromides, yield thecorresponding lower alkenyl products. Similarly, other products ofExamples 1 and 2 yield the corresponding 17alower alkenyl compounds bythis procedure.

Example 11 To a solution of 1 g. of lithium aluminum hydride in ml. ofanhydrous tetrahydrofuran is continuously bubbled a slow current ofpurified acetylene for one hour. Thereafter, 1 g. of 3 (4'methoxytetrahydropyran-4'- yloxy)-estra-1,3,5 (10)-trien-17-one in 10ml. of tetrahydrofuran is added and the reaction mixture stirred at roomtemperature for four hours. Eight milliliters of water are then addedand the mixture stirred for 30 minutes. The mixture is then filtered andthe organic filtrate evaporated to yield 3(4-methoxytetrahydropyran-4'-yloxy)-17-ethynylestra-1,3,5(10)-trien-l7fl-ol which is recrystallized fromacetonezhexane.

Following the same procedure, 3-(4'-methoxytetrahydropyran-4'-yloxy)-17a-ethynyl-18-methylestra- 1,3 ,5(10)- trien-17B-ol, 1methyl-3-(4'-methoxytetrahydropyran-4'- yloxy) 17ccethynylestra-1,3,5(10)-trien-17 3-ol, 3-(4'- methoxytetrahydropyran4'-yloxy)-7a-methyl-17u-ethynylestra-1,3,5 (10)-trien-17fi-ol and3-(4'-methoxytetrahydropyran-4'-yloxy) -17a-ethynylestra-1,3,5 10) ,7tetraen- 17fi-ol, for example, are obtained from the corresponding17-ketones. Similarly, other 17a-ethyny1-17/3-ols having groups at C-1,C-7, C-16 and C-l8 as indicated with respect to Formula VI can beprepared from the corresponding 17-ket0ne products of Examples 1 and 2,e.g. 1,3 bis(4' methoxytetrahydropyran4-yloxy)-17aethynylestra-l,3,5(10)-trien-17-ol, etc.

Example 12 To a refluxing solution of 6.2 g. of3-(4-methoxytetrahydropyran 4 yloxy)17u-ethynyl-1718-acetoxyestra-1,3,5(10)-triene in 15 ml. of anhydrousdiglyme, there is added dropwise over a period of about 80 minutes aheated (about 60 C.) solution of 20.72 g. of sodiumchlorodifiuoroacetate in 50 ml. of anhydrous diglyme under nitrogen withstirring. After all the sodium chlorodifluoroacetate is added, thereaction mixture is cooled and filtered. The filtrate is evaporated todryness to reduced pressure. The residue is dissolved in hexane andchromatographed on 300 g. of Florisil (synthetic magnesium silicate),eluting with hexane:ether, to furnish 3- (4' methoxytetrahydropyran4-yloxy)-17ot-(2",2-difluorocyclopropenyl) -17;8-acetoxyestra-1,3 ,5(10) -triene.

Following the same procedure but replacing the 3-(4-methoxytetrahydropyran 4'-yloxy)-17 x-ethynyl-17fi-ace toxyestra 1,3,5(10)-triene with the corresponding compounds having other substituentsat C1, C-7, C-16 and C-18 as described with respect to Formula VI(products of Example 11) yields the corresponding17oc-(2",2"-difiuorocyclopropenyl) products.

Example 13 Following the procedure of Example 7 but replacing 3-(4'rnethoxytetrahydropyran-4'-yloxy)-estra-1,3,5(10), 7-tetraen-l7 3-olwith 3 (4'-methoxytetrahydropyran-4- yloxy) 17aethynylestra-1,3,5(10)-trien-17fi-ol and 3- (4'methoxytetrahydropyran-4-yloxy)-17a-ethynylestra-1,3,5(10),7-tetraen-17fi-ol, the corresponding 17fi-acetates areobtained, e.g. 3(4'-methoxytetrahydropyran-4'-yloxy)-17a-ethynyl-17B-acetoxyestra-1,3,5(10)triene and 3-(4-methoxytetrahydropyran-4yloxy) -17a-ethynyl-17B-acetoxyestra-1,3,5 (10),7-tetraene.

Following the same procedure using other acid chlorides and/or 17B-olshaving groups at C-1, C-7, C-16 and C-18 as indicated in Formula VI areconverted to the corresponding NIB-esters, e.g. 1,3bis(4'-methoxytetrahydropyran-4'-yloxy)-17u-ethynyl-17,8 acetoxyestra-1,3,5 (10)-triene, etc. When reactive hydroxy groups other than at 17/3are present, the diacetyl products are obtained with a correspondingmolar excess of reactants; the monoacetyl products are formed by using acorresponding molar concentration of reactants and separating thedesired products by conventional chromatography from the ester mixtureformed.

Example 14 Following the procedures of Example 1 but replacingestra-1,3,5 (10)-trien-3-o1-17-one with 3-(4'-methoxytetrahydropyran 4yloxy)-17a-ethynylestra-1,3,5 (10)-trien 17/3-01, 3,175bis(4-methoxytetrahydropyran-4-yloxy)- 17a-ethynylestra-1,3,5(10)-triene is obtained.

Following the procedures of Example 2 but replacing estra 1,3,5(l),7tetraen 3 ol 17-one with 3-(4'- methoxytetrahydropyran 4' yloxy) 17aethynylestra- 1,3,5(),7 tetraen-17/3-ol yields the corresponding 3, 17,8bis(4'-methoxytetrahydropyran-4-yloxy)-17a-ethynylestra-1,3,5( 10),7-tetraene.

Similarly, other 3,17fl-bis (4'-alkoxytetrahydropyran-4'- yloxy) ethersare obtained from other 4-alkoxy-5',6-di- 18 hydro-2H-pyrans.Substituting other estra-1,3,5( 10)-trien- 17B-ols andestra-1,3,5(l0),7-tetraen-l7;3-ols at C-1, C-7, C-l6 and C-l8 asindicated in Formula VI (products of Examples 3, 4 and 9-11 withreactive hydroxyl groups other than at C-17 3 suitably protected) yieldsthe corresponding substituted 3,17/3-bisethers (compounds of FormulaVIII).

Example 15 A solution of 8.5 g. of 1,2-dichloroethylene in 50 m1. ofanhydrous ether is added in a dropwise fashion under nitrogen and at 0C. over a 30 minute period to a stirred solution of 15 ml. of 1.4 Nmethyl lithium in anhydrous ether. After stirring for an additionalminutes at room temperature, a solution of 0.5 g. of3-(4-methoxytetrahydropyran-4-yloxy)-estra- 1,3,5 (10)-trien-17-one in20 ml. of anhydrous ether is added in a dropwise fashion with stirringover a 15 minute period. Stirring at room temperature is continued for18 hours and the reaction mixture. is then poured into ice water andextracted with ether. These extracts are washed with water, dried oversodium sulfate and concentrated under reduced pressure. The residue ischromatographed on alkaline alumina with 8:2 hexanezether to yield3-(4-methoxytetrahydropyran- 4'-yloxy)-17a-chloroethynylestra 1,3,5 10)trien-IZB-ol which may be recrystallized from methanol.

By the same procedure but replacing 1,2-dichloroethylene with otherhalogenated ethylenes, such as 1-chloro-2- fluoroethylene,1,2-dibromoethylene, and the like, provide the corresponding compoundwith a l7u-fiuoroethynyl substituent or 17a-bromoethynyl substituent,respectively.

Following the same procedure but replacing the 3-(4'-methoxytetrahydropyran-4'-yloxy)-estra 1,3,5 10)-trien- 17-one with thecorresponding 17-keto compounds having substituents at C-1, C-7, C-16and C18 as indicated in Formula V, the corresponding 17u-haloethylenecompounds are obtained.

Example 16 Following the procedure of Example 3 but replacing3-(4-methoxytetrahydropyran-4-yloxy) estra-1,3,5(10) trien-17-one withestral,3,5(10)-trien-3-ol-17-one yieldsestra-1,3,5(10)-triene-3,17-diol. By the same procedure,estra-1,3,5(10)-triene-3,17-diols having hydrogen, methoxy and hydroxy,at C-1; hydrogen or methyl at C-7; hydrogen or hydroxy at C-16; andhydrogen or methyl at C18 are obtained from the correspondingestra-1,3,5 (10)-trien-3-ol-17-ones.

Example 17 Following the procedure of Example 1 but replacingestra-1,3,5(10)-trien-3-ol-17-one with estra-1,3,5(10-triene-3,17-dioland using 4 ml. of the 4'-methoxy-5,6-di- 'hydro-2H-pyran instead of 2m1. yields 3,1719-bis(4'-methoxytetrahydropyran-4-yloxy)-estra-1,3,5 10)-triene.

Following the procedure of Example 2 but replacingestra-1,3,5(10),7-tetraen-3-ol-17-one with estra-1,3,5(-10),7-tetraen-3,17 8-diol and using 4 ml. of the 4'-methoxy-5',6'-dihydro-2H-pyran instead of 2 ml. yields 3,17 8-bis(4'-methoxytetrahydropyran-4'-yloxy) estra-1,3,5(10),7- tetraene.

By the same procedures,3,17B-bis(4-methoxytetrahydropyran-4'-yloxy)-estra-1,3,5(10)-trienes and3,17,6-bis (4'-methoxytetrahydropyran 4' yloxy)-estra-1,3,5(10),7-tetraenes having hydrogen, methoxy, acetoxy, or other ester groups atC-1; hydrogen or methyl at C-7; hydrogen, acetoxy, or other ester at(3-16; and hydrogen or methyl at C-18 are obtained from thecorresponding diols.

Example 18 Following the procedure of Example 9 but replacing 3-(4-methoxytetrahydropyran 4'-yloxy)-estra-1,3 ,5 10)- trien-17-one withestra-1,3,5(10)-trien-3-ol-17-one or estra-1,3,5(10),7-tetraen-3-ol 17one yields 17wmethylestra-1,3,5(10)-triene-3,17fl-diol and17u-methylestra-L3, 5 10),7-tetraene-3,17;3-diol, respectively.

1 9 Substituting these products for estra-l,3,5(10)-triene-3, 17,8-dioland estra-1,3,5 l),7-tetraene-3,17fl-diol in the process of Example 17yields 3,l7,8-bis(4-methoxytetra hydropyran-4-yloxy)-17a-methylestra1,3,5 triene and 3, l7,8-bis(4'methoxytetrahydropyran-4-yloxy)-17txmethylestra- 1,3,5 10) ,7-tetraene,respectively.

Example 19 Following the procedure of Example 10 but replacing3-(4'-methoxytetrahydropyran 4'-yloxy)-estra-1,3,5(10)- trien-17-onewith estra 1,3,5(10) trien-3-ol-17-one or estra-1,3,5(10),7-tetraen 3 ol17-one yields 17a-vinylestra-1,3,5(10) triene 3,17-diol or17u-vinylestra-1,3,5 (10) ,7-tetraene-3 ,17-diol, respectively.

Following the procedure of Example 17 but replacingestra-1,3,5(10)-triene 3,17 -diol and estra-l,3,5(10),7-tetraene-3,l7p-diol with the last named l7a-vinyl compounds yields 3,17Bbis(4 methoxytetrahydropyran-4'- yloxy)-17 x-vinylestra-l,3,5(10)-trieneand 3,l7B-bis(4- methoxytetrahydropyran 4' yloxy)-17a-vinylestra-1,3,5(10,7-tetraene, respectively.

Example 20 Following the procedure of Example 11 but replacing 3-(4'methoxytetrahydropyran 4 yloxy) estra 1,3,5 10)-trien-17-one withestra-l,3,5 10 -trien-3-ol-l7-orte orestra-1,3,5(10),7-tetraen-3-ol-17-one yields 17a-ethynylestra-1,3,5( l0)-triene-3,17-diol and l7a-ethynylestra- 1,3,5(10),7-tetraene-3,17-diol,respectively.

Substituting these products for estra-1,3,5 10)-triene- 3,17-diol andestra-1,3,5(10),7-tetraene-3,17p-diol in the process of Example 17yields 3,17,8-bis(4-methoxytetrahydr0pyran-4-yloxy)-17a-ethynylestra1,3,5(10) triene and 3,17fl-bis(4-methoxytetrahydropyran-4'-yloxy)-17uethynylestra-1,3,5(10),7-tetraene.

Example 21 Following the procedure of Example 15 but replacing 3 (4'methoxytetrahydropyran 4 yloxy) estra-1,3,5 10)-trien-17-one withestra-1,3,5(10)-trien-3-ol-17-one orestra-1,3,5(10),7-tetraen-3-ol-17-one yields 17a-chloroethynylestra-1,3,5(10) triene 3,17-diol and17a-chloroethynylestra-1,3 ,5( 10 ,7-tetraene-3, l 7-diol, respectively.

Substituting these products for estra-1,3,5(10)-triene- 3,l7fl-diol andestra-l,3,5(10),7-tetraene-3,l7{3-diol in the procedure of Example 17yields 3,l7 3-bis(4-methoxytetrahydropyran-4-yloxy) 17ozchloroethynylestra-1,3,5 (10)-triene and3,17B-bis(4'-methoxytetrahydropyran-4-yloxy)-17a-chloroethynylestra-1,3,5 (10),7 tetraenes, respectively.

Example 22 Following the procedure of Example 12 but replacing3-(4'-methoxytetrahydropyran-4-yloxy) 17oz ethynyl-3,17fl-diacetoxyestra-1,3,5 10)-triene with 17m-ethynyl-3,17B-diacetoxyestra 1,3,5(10) triene or 17a-ethynyl- 3,17/3diacetoxyestra-1,3,5(10),7-tetraene yields 170:- (2" ,2"difluorocyclopropenyl) 3,175 diacetoxyestra- 1,3,5(10)-triene and17a-(2",2"-difluorocyclopropenyl)- 3,17fi-diacetoxyestra-1,3,5 10),7-tetraene, respectively.

A solution of 0.17 g. of potassium hydroxide in 0.2 ml. of water and 2.5ml. of methanol is added over 30 minutes to a refluxing solution of 1 g.of 17a-(2",2"-difluorocyclopropenyl) 3,1719 diacetoxyestra-1,3,5(10)-triene or 170:(2",2"-difiuorocyclopropenyl)-3,l7fl-didiacetoxyestra-1,3,5(10),7-tetraene in 30 ml. of methanol under nitrogen. The solution isrefluxed for two hours, cooled, neutralized with acetic acid andconcentrated under reduced pressure. After the addition of water, thesolid which forms is collected by filtration and drived to yield 17oz(2",2" difluorocyclopropenyl) estra- 1,3,5(10)-triene-3,l7fi-diol or17a-(2",2-difluorocyclopropenyl)-estra-1,3,5(10),7-tetraene 3,17/3 diolrespectively, which is recrystallized from acetonezhexane.

Repeating the procedure of Example 1 but replacing 2.0estra-1,3,5(10)-trien-3-ol-17-one with 17a-(2",2"difluorocyclopropenyl)-estra-1,3,5(10)-triene 3,17 diol and using 4 ml.instead of 2 ml. of 4'-methoxy-5,6-dihydro-2H-pyran yields 3,178-bis(4'-methoxytetrahydropyran-4-yloxy) 170a (2",2"difluorocyclopropenyl)- estra-1,3,5( 10 -triene.

Repeating the procedure of Example 2 but replacingestra-1,3,5(10),7-tetraen-3-ol-17-one with 17oz (2",2"-difluorocyclopropenyl) estra 1,3,5(l0),7 tetraene- 3,17 8-dio1 and using4 ml. instead of 2 ml. of 4'-methoxy- 5,6'-dihydro-2H-pyran yields3,l7,6bis(4-methoxytetra hydropyran-4-yloxy) 17oz (2",2difluorocyclopropeny1)-estra-1,3,5 10 ,7 -tetraene.

Following the same procedure, other 3,1718-bis(4'-methoxytetrahydropyran-4-yloxy)-17u-(2",2"difluorocyclopropenyl)-estratrienes and estratetraenes having groups atC1, C7, Cl6 and C-18 as indicated in Formula VIII are obtained.

Example 23 Following the procedure of Example 4, paragraph 1, butreplacing 3 (4-methoxytetrahydropyran-4-yloxy)-estra-1,3,5(10)-trien-17/3-ol with estra-1,3,5(10)-trien-3- ol-17-one orestra-1,3,5(1 0),7-tetraen-3-ol-17-one, 3-cyclopentoxyestra-1,3,5(10)-trien-17-one or 3-cyclopentoxyestra-1,3,5(10),7-tetraen-17-one areobtained. Repeating this procedure with estratrien-3-ol-l7-0nes havinghydrogen, methyl or methoxy groups at C1; hydrogen or methyl groups atC7; hydrogen, methoxy or hydrolyzable esters at C-l6u; and hydrogen ormethyl groups at C18 yields the corresponding3-cyclopentoxyestratrien-(or -tetraen)-17-ones, e.g. 3-cyclopentoxy-18-methylestra-1,3,5(10)-trien-17-one.

To a refluxing solution of 5 g. of estra-1,3,5 (10)-trien- 3-ol-17-oneor estra-1,3,5-(10),7-tetraen-3-ol-17-one in 500 ml. of ethanol areadded over a 30 minute period 20 ml. of dimethyl sulfate and g. ofpotassium hydroxide in 50 ml. of water, 5 ml. portions of each beingalternatively added. The mixture is then refluxed for 45 minutes, cooledand poured into ice water. The solid which forms upon neutralizationwith dilute acetic acid is collected, washed with water and dried toyield 3- methoxyestra-1,3,5 10)-trien-17-one and 3-methoxyestra- 1,3,510) ,7-tetraen-17-one, respectively, which is recrystallized fromchloroformzmethanol. Following the same procedure, ethers havinghydrogen, methyl or methoxy groups at C1; hydrogen or methyl groups atC7; hydrogen, methoxy or hydrolyzable ester groups at C16a; and hydrogenor methyl groups at C18 are obtained from the corresponding 3-hydroxycompounds.

Example 24 Two milliliters of dihydropyran are added to a solution of 1g. of estra-1,3,5(10)-trien-3-ol-17-one in 15 ml. of benzene. About 1ml. is removed by distillation to remove moisture and 0.4 g. ofp-toluenesulfonic acid is added to the cooled solution. This mixture isallowed to stand at room temperature for four days, and is then washedwith aqueous sodium carbonate solution and water, dried and evaporated.The residue is chromatographed on neutral alumina, eluting with hexane,to yield 3-tetrahydropyran-2'-yloxyestra 1,3,5(10) trien 17-one which isrecrystallized from pentane.

Two milliliters of dihydropyran are added to a solu-- tion of 1 g. ofestra-1,3,5 (1 0),7-tetraen-3-ol-17-one in 15 ml. of benzene. About 1ml. is removed by distillation to remove moisture and 0.4 g. ofp-toluenesulfonyl chloride is added to the cooled solution. This mixtureis allowed to stand at room temperature for four clays, and is thenwashed with aqueous sodium carbonate solution and water, dried andevaporated. The residue is chromatographed on neutral alumina, elutingwith hexane, to yield 3-tetrahydropyran-2'-yloxyestra-1,3,5(l0),7-tetraen-17-one which is recrystallized from pentane.

Following the same procedure with substituted estra- 1,3,5(10)-trien-3-o1-17-ones and estra-1,3,5(10),7-tetraen- 3-ol-17-oneshaving hydrogen, methyl, methoxy or hydrolyzable ester groups at C-1;hydrogen or methyl groups at C-7; hydrogen, methoxy or hydrolyzableester groups at 016a; and hydrogen or methyl groups at C18 yields thecorresponding S-tetrahydropyran 2 yloxy compounds, e.g.3-tetrahydropyran-2-yloxy-l8-methylestra- 1,3,5 10)-trien-17-one.

Example 25 Following the procedure of Example 3 but replacing 3-(4'-methoxytetrahydropyran-4-yloxy) estra 1,3,5(10)- trien-17-one withestra-1,3,5(10)-trien-3-ol-17-one orestra-1,3,5(10)-7-tetraen-3-ol-17-one, estra 1,3,5(10)- trien-3,173-diol or estra-1,3,5 (10),7-tetraen-3,17,8-diol, respectively, areobtained.

Following the same procedure, 3,17B-diols and 3-ether- 17B-o1s havinghydrogen, methyl, hydroxy or methoxy at C1; hydrogen or methyl groups at-7; hydrogen, methoxy or hydroxy at C-16a; and hydrogen or methyl groupsat C-18 are obtained from the corresponding 17- ones, e.g.18-methylestra-1,3,5(10)-trien-3,17,9-diol, estra- 1,3,5(10)-trien-3,16o=,175-triol, 7a-methylestra-1,3,5(10)-trien-3,l7fl-diol, 1-methylestra-l,3,5(10) trien 3,17/3- diol,estra-1,3,5()-trien-1,3,17fi-triol, 3-methoxyestra- 1,3,5(10)-trien-17p-o1, 3 cyclopentoxy-l8-methylestra-1,3,5(10)-trien-175-0l, estra-1,3,5 (10)-trien-3,17fi-diol, 3-tetrahydropyran-2'-yloxyestra-1,3 ,5 (10)-trien-17B-o1, 3-tetrahydropyran-Z-yloxy-18-methylestra-1,3,5( 10) trien- 17/3-01, etc.

Example 26 Repeating the procedure of Example 9 but replacing3-(4'-methoxytetrahydropyran 4' yloxy)-estra-1,3,5- (10)-trien-17-0newith estra-1,3,5(10)-trien-3-ol-17-one orestra-1,3,5(10),7-tetraen-3-ol-17-one, 17a methylestra-1,3,5(10)-trien-3,7,8-diol and 170: methy1estra-1,3,5(10),7-tetraen-3,17;8-dio1, respectively, are obtained.

Example 27 Repeating the procedure of Example 9 but replacing 3(4'-methoxytetrahydropyran-4-y1oxy)-estra-1,3,5(10)- trien-17-one withestra-1,3,5(10)-trien-3-ol-17-one or estra-1,3,5(l0),7-tetraen-3-l7-one,17a methylestra-l,3,5- 10) -trien-3,17B-diol and 17a-vinylestra1,3,5 l0),7-tetraen-3,17fi-diol, respectively, are obtained. Similarly, other17a-(1ower)-a1kenyl derivatives are obtained using the respective loweralkenyl magnesium bromides in the above procedure.

Example 28 Repeating the procedure of Example 11 but replacing 3(4'-methoxytetrahydropyran-4-yloxy)-estra-1,3,5- (10 -trien-17-one withestra-1,3,5(10)-trien-3-o1-l7-one or estra-1,3,5 10),7-tetraen-3-o1-l7-one, Not-ethynylestra- 1,3,5(l0) trien-3,175 diol and17a-ethynylestra-1,3,5- (10),7-tetraen-3,17/3-dio1, respectively, areobtained. By the same procedure using as starting materials havinghydrogen, methyl or methoxy groups at Cl; ether or hydroxy groups atC-3; hydrogen or methyl groups at C7; hydrogen, methoxy or hydroxygroups at Cl6oc; and hydrogen or methyl groups at C-18, thecorresponding 17a-ethyny1 compounds are obtained, e.g.Hot-ethynyl-18-methylestra-l,3,5 10) -trien-3,17/8-diol,flat-ethynylestra-1,3,5(10) trien 3,l'6oc,17B-tl'iO1, Una-ethynylestra-1,3,5 l0) -trien-1,3,17B-trio1, 3.-methoxy-Hot-ethynylestra-1,3,5(10)-trien-l7B-ol, 3 cyclopentoxy-Not-ethynylestra-1,3,5(10)-trien-l7;8-ol, 3 cyclopentoxy-l7a-ethynyl-l 8-methy1estra-1,3,5 (10)-trien-17/3-o1, etc.

Example 29 Repeating the procedure of Example but replacing 3(4'-rnethoxytetrahydropyran-4'-yloxy)-estra1,3,5- (10)-trien-17-one withestra-1,3,5(10)-trien-3-ol-l7-one or estra-l,3,5 10),7-tetraen-3-o1-17-one, 17a-ch1oroethynylestra-l,3,510)-trien-3,17fi-diol and 17a-chloroethynyl- 221,3,5(10),7-tetraen-3,l7fl-dio1 are obtained. Repeating the procedurewith 3-methoxyestra 1,3,5(l0) trien-l7fi-ol yields3-methoxy-17u-chloroethynylestra-l ,3 ,5( 10 -trien- 1713-01. Similarly,products having other substituents at C1, C7, C16 and C18 are obtainedfrom the corresponding substituted 17-ones by this procedure.

Example 30 Repeating the procedure of Example 5 but replacing 3(4'-methoxytetrahydropyran-4-yloxy)-estra-1,3,5 10)- trien-l7B-ol with17u-ethyny1estra-1,3,5(10)-trien-3,171S- diol,3,17B-diacetoxy-17a-ethynylestra-1,3,5(10)-trien is obtained. Followingthe procedure of Example 7 but replacing 3-(4'-methoxytetrahydropyran 4'yloxy)-estra- 1,3,5(10),7-tetraen-l7fl-o1 with Not-ethynylestra 1,3,5-(l0),7-tetraen-3,l7B-di01, 3,17B-diacetoxy 17ccethynylestra-1,3,5(10),7-tetraene is obtained.

Following the procedure of Example 12 but replacing 3-(4'-methoxytetrahydropyran-4'-y1oxy) -17ot-ethyny1-17;8-acetoxyestra-l,3,5(10)-triene with3,17fi-diacetoxy-17aethynylestra-1,3,5(10)-triene or3,17/3-diacetoxy-1h-ethynylestra-1,3,5(10),7 tetraene,3,l7/3-diacetoxy-17a-(2", 2 difiuorocyclopropenyl) estra-1,3,5(10)triene and 3,1713 diacetoxy l7u-(2",2" difiuorocyclopropenyl)-estra-1,3,5(l0),7-tetrane, respectively, are obtained.

Repeating these same procedures with the other substituted compoundsrepresented by Formula IV yields the corresponding C-l, C-7, C16 and C18substituted products having 17oz (2",2 difiuorocyclopropenyl) groups asdescribed with respect to Formula X.

Example 31 A mixture of 1 g. of estra-1,3,5 (10)-triene-3,17;3-diol, 4ml. of pyridine and 2 ml. of acetic anhydride is allowed to stand atroom temperature for 15 hours. The mixture is then poured into ice Waterand the solid which forms is collected by filtration, washed with waterand dried. The mixture is chromatographed on neutral alumina, elutingwith ether2hexane, to yield 3-acetoxyestra- 1,3,5 10) -trien-17,B-ol.

Similarly, C3 esters having hydrogen, methyl, acyloxy or methoxy groupsat Cl; hydrogen or methyl groups at C7; hydrogen, methoxy orhydrolyza-ble esters at C16u; hydrogen, lower alkyl, lower alkenyl,lower alkynyl, lower haloalkynyl and difiuorocyclopropenyl at C17a; andhydrogen or methyl groups at Cl8 are obtained from the corresponding3,17fl-dihydroxy compounds as listed below:

3-3.CtOXY-l7oc (2",2" difiuorocyclopropenyl) -estra- 1,3,5 1O -trien-173ol,

3-acetoxy-18-methylestra-1,3 ,5 l O -trien-l 7,801,

3, 1 6 ot-diacetoxyestral ,3 ,5 10 -trien-17 8-o1,

3-acetoxy-17a-ethynylestra-1,3,5 10 -trien-o1 3-acetoxy-l7,B,17a-ethynyl 18 methylestral ,3 ,5 10 trien-17601,

3,16u-diacetoxy 17cc ethynylestra 1,3,5( 10)-trien- 175-01,

3-acetoxy-7a-methylestra-l ,3,5 10 -trien-o1,

l-methyl-3-acetoxyestra-1,3,5 10)-trien-17fl-ol,

1,3-diacetoxyestra-l,3,5 10)-trien-17/8-o1,

1,3 diacetoxy-17a-ethynylestra-1,3,5 (10)-trien- 1 75-01, etc.

To a solution of 5 g. of estra-1,3,5(lO)-triene-3,17B- diol in m1. ofanhydrous benzene are added 1 g. of p-toluenesulfonic acid and 10 ml. ofundecenoic anhydride. The mixture is allowed to stand for 24 hours atroom temperature and poured with stirring into ice and water. Theorganic phase is separated, washed with 10% sodium carbonate solutionand with water, and dried. The mixture is then chromatographed onneutral alumina, eluting with etherzhexane, to yield3-undecenoyloxyestra-l,3,5(10)-trien-17fi-ol. Similarly, estra1,3,5(10)- triene-3,17fi-diols having groups at Cl, C16, C17a. and C18as indicated in Formula VII are converted to the corresponding 3-estersby this procedure.

A solution of 1 g. of estra-1,3,5(10),7-tetraene-3, 17pdiol in 16 ml. ofanhydrous ether is treated with 7.5 molar equivalents of ethylmagnesiumbromide in ether and, after a few minutes, with 7.5 after a few minutes,with 7.5 molar equivalents of acetyl chloride. The mixture is allowed tostand at room temperature for 15 hours, then diluted with water andextracted with methylene chloride. The extracts are washed with water toneutrality, dried and evaporated. The residue is chromatographed onneutral alumina, eluting with ether:hexane, to yield 3 acetoxyestra1,3,5(10),7 tetraen 17B which is recrystallized from acetone :hexane.

A mixture of 2 g. of estra-1,3,5(10)-triene-3,17fi-diol in 8 ml. ofpyridine and an equivalent molar amount of benzoyl chloride is heated atsteam bath temperatures for 30 minutes. The mixture is then poured intoice water and the solid which forms is collected by filtration, washedwith water and dried. The mixture is chromatographed on neutral alumina,eluting with etherzhexane, to yield 3 benzoyloxyestra 1,3,5(10) trien17/3 01 which is recrystallized from acetonezhexane. Repeating thisprocedure with estra 1,3,5(10),7 tetraene 3,176 diol yields3-benzoyloxyestra-1,3,5(10),7 tetraen 17B 01. Following the sameprocedure, estratrien-17fl-ols and estratetraen-17B-ols having groups atC-1, C-7, Cl6, Cl7a and C-18 as indicated in Formula VII are convertedto the corresponding 3-benzoyloxy compounds.

Example 32 Following the procedure of Example 1 but replacing estra1,3,5(10) trien 3 ol 17 one with 3 acetoxyestra 1,3,5(10) trien 17 ol, 3acetoxy 17,8 (4'- methoxytetrahydropyran 4 yloxy) estra 1,3,5(l)- trieneis obtained. Following the procedure of Example 2 but replacing estra1,3,5(),7 tetraen 3 ol 17 one with 3 acetoxyestra l,3,5(l0),7 tetraen 17ol, 3- acetoxy 17/3 (4 methoxytetrahydropyran 4 yloxy)-estra-1,3,5(10),7-tetraene is obtained. Repeating these procedures with17-hydroxy compounds having acyloxy and ether groups at C-3; hydrogen,methyl, acetoxy or methoxy groups at C-l; hydrogen or methyl groups atC-7; hydrogen, methoxy or hydrolyzable esters at Cl6a; hydrogen, loweralkyl, lower alkenyl, lower alkynyl, lower haloalkenyl anddifiuorocyclopropenyl groups at C-17a; and hydrogen or methyl groups atC-18, the corresponding 17,8-(4-methoxytetrahydropyran 4' yloxy) ethersare obtained, e.g.

3-acetoxy-17fl-(4'-methoxytetrahydropyran-4-yloxy) 17a-2",2-difluorocyclopropenyl) -estra- 1,3 ,5 l0 -triene,

3-acetoxy-17fi- (4'-methoxytetrahydropyran-4'-yloxy)18-methylestra-1,3,5( 10) -triene,

3,16a-diacetoxy-17fl-(4'-methoxytetrahydropyran-4'- yloxy)-estra-1,3 ,510) -triene,

3 -acetoxy-17,8-(4'-methoxytetrahydropyran-4'-yloxy) 17 a-ethynylestra-1 ,3 ,5 1O -triene,

3-acetoxy-17,B-(4'-methoxytetrahydropyran-4-yloxy)17u-ethynyl-18-methylestra-1,3 ,5 10 -triene,

3 1 6u-diacetoxy- 17 ,8- 4'-methoxytetrahydropyran-4'- yloxy) -l7x-ethynylestra-1,3 ,5 10 -triene,

3-acetoxy-7a-methyl-17fl- (4'-methoxytetrahydropyran- 4'-yloxy)-estra-1,3 ,5 1O -triene,

1-methyl-3 -acetoxy-17,B- 4'-methoxytetrahydropyran- 4'-yloxy) -estral,3 ,5 10) -triene,

1,3 -diacetoxy-17B-(4'-methoxytetrahydropyran-4'- ylox y) -estral ,3 ,510 -triene,

1,3 -diacetoxy- 17 ,8- 4'-methoxytetrahydropyran-4'-yloxy)-17a-ethynylestra-1,3 ,5 10 -triene,

3-methoxy-17fi-(4-methoxytetrahydropyran-4'- yloxy) -17u-ethynylestra-l,3,5( 10) -triene,

3 -rnethoxyl7fl- 4'-methoxytetrahyd ropyran-4- yloxy) estra-1,3 ,5 1 O-triene,

3-methoxy-17/3- (4-methoxytetrahydropyran-4'-yloxy)l7ot-chloroethylnylestra- 1,3,5 l0) -triene,

24 3 -cyclopentyloxy-17{3- 4'-methoxytetrahydr0pyran-4'- yloxy)-estra-1,3 ,5 l0) -triene,3cyclopentyloxy-17,8-(4'-methoxytetrahydropyran-4'-yloxy)-l8-methylestra-l,3,5(10)-triene, 3-cyclopentyloxy- 17 B-4-methoxytetrahydropyran-4- yloxy)-17a-ethyny1estra-1,3,5(10)-triene,3-cyclopentyloxy-17/3- (4-methoxytetrahydropyran-4'-yloxy)-17u-ethynyl-18-methylestra-1,3 ,5 1 0 -triene, 3-benzoyloxy-17(3-(4'-methoxytetrahydropyran-4'- yloxy) -estra-1,3 ,5 10-triene, 3 -tetrahydropyran-2'-yloxy-17,6-4-methoxytetrahydropyran-4'-yloxy) -estra-1,3 ,5 10)-triene, and3-tetrahydropyran-2'-y1oxy- 17 [1- (4-methoxytetrahydropyran-4-yloxy) -18-methylestra-1,3 ,5 10) -triene,

Example 33 A solution of 0.17 g. of potassium hydroxide in 0.2 ml. ofwater and 2.5 ml. of methanol is added over 30 minutes to a refluxingsolution of 1 g. of 3-acetoxy-17fi-(4'- methoxytetrahydropyran 4' yloxy)estra 1,3,5(10)- triene or 3-acetoxy 17B (4-methoxytetrahydropyran-4'-yloxy)estra-1,3,5(10),7-tetraene in 30 ml. of methanol undernitrogen. The solution is refluxed for two hours, cooled, neutralizedwith dilute acetic acid, and concentrated under reduced pressure. Afterthe addition of water, the solid which forms is collected by filtrationand dried to yield 17,8-(4-1nethoxytetrahydropyran-4'- yloxy) estra1,3,5(10) trien 3 01 or 17,6-(4'- methoxytetrahydropyran 4' yloxy) estra1,3,5(10), 7-tetraen-3-ol, respectively which is recrystallized fromacetone: hexane.

Repeating this procedure with the other acylated products obtained inthe procedure of Example 32 yields hydroxy compounds having hydrogen,methyl, methoxy of hydroxy groups at C-1; hydrogen or methyl groups atC-7; hydrogen, methoxy or hydroxy groups at 0-16; and hydrogen or methylgroups at C-18, for example:

17 5- 4-methoxytetrahydropyran-4'-yloxy 1 8- methyl-estra-1,3 ,5 10-trien-3 -ol,

17B- (4'-methoxytetrahydropyran-4-yloxy) -estra- 1,3,510)-triene-2,16a-diol 17 (4-methoxytetrahydropyran-4-yloxy)17aethynyl-estra- 1,3,5 10 -trien-3-ol,

17,6-(4'-methoxytetrahydropyran-4-yloxy) 17aethynyl-18-methylestra-1,3,510) -trien-3-ol,

17 3-(4-methoxytetrahydropyran-4'-yloxy) 17aethy1nyl-estra-1,3 ,510)-triene-3,16a,diol,

7u-methyl- 17 fl- 4-methoxytetrahydropyran-4'-yloxy estra-1,3 ,5( 10)-trien-3 -01,

1-methy1-17fl- (4'-methoxytetrahydropyran-4'-yloxy estra-1,3,5(10)-trien-3 -ol,

1-hydroxy-17B- (4-methoxytetrahydropyran-4'-yloxy estra-1,3,5 1 0-trien-3 -ol,

17B-(4'-rnethoxytetrahydropyran-4'-yloxy) -17a-(2",2"-difluorocyclopropenyl) -estra-1,3,5 10) -trien3 -01,

17,8- (4'-methoxytetrahydropyran-4'-yloxy) -17u-Chl010-ethynylestra-1,3,5(10)-trien-3-ol, etc.

What is claimed is:

1. A 4'-(lower)alkoxytetrahydropyran-4-yl ether of anestra-1,3,5(10)-triene having at position C-l, a member selected fromthe group consisting of hydrogen, methyl, methoxy, hydroxy andconventional hydrolyzable esters thereof, and4'-(lower)alkoxytetrahydropyran-4- yloxy; at position C7,8 a memberselected from the group consisting of a single bond and a double bond;at position C-7, a member selected from the group consisting of hydrogenand methyl, said last named member having either a or 8 configurationwhen the bond at C-7,8, is a single bond; at position C-16m when thebond at C-7,8 is a single bond, a member selected from the groupconsisting of hydrogen, hydroxy and conventional hydrolyzable estersthereof and when the bond at C7,8 is a double bond, hydrogen is atposition C4611; at position C17oz, a member selected from the groupconsisting of hydrogen, lower alkyl, lower alkenyl, lower haloalkenyl,lower alkynyl, 2",2"-difiuorocyclopropenyl and in conjunction withCl7,8, keto; at positions C-3 and C-l7fi, members selected from thegroup consisting of hydrogen, hydroxy and conventional hydrolyzableesters thereof, lower alkoxy, lower cycloalkoxy, lower cycloalkenyloxy,tetrahydropyran-2-yloxy and 4-(lower) alkoxytetrahydropyran-4-yloxy, atleast one of said members at said C-3 and C-175 positions being a4-(lower) alkoxytetrahydropyran-4-yloxy group.

2. The steroid ether of claim 1 wherein the ether is 3-(4'-methoxytetrahydropyran-4'-yloxy) estra-1,3,5()- trien-17-one.

3. The steroid ether of claim 1 wherein the ether is3-(4'-methoxytetrahydropyran-4'-yloxy) estra-1,3,5(10)- trien-17/3-o1.

4. The steroid ether of claim 1 wherein the ether is3-(4'-methoxytetrahydropyran-4'-yloxy) 17a ethynylestra-l,3,5 (10)-trien-17fl-o1.

5. The steroid ether of claim 1 wherein the ether is3-(4'-methoxytetrahydropyran-4-yloxy)Jot-methyl 17aethynylestra-1,3,5(10) -trien-17 3o1.

6. The steroid ether of claim 1 wherein the ether is 3(4-methoXytetrahydropyran-4'-yloXy) 17,8cyclopentoxyestra-1,3,5(10)-trien-17B-ol.

7. The steroid ether of claim 1 wherein the ether is 3(4'-methoxytetrahydropyran-4'-yloxy) -estra-l,3,5 (10),7-tetraen-17-one.

8. The steroid ether of claim 1 wherein the ether is3,l7fi-bis(4'-methoxytetrahydropyran 4' yloxy)-estra- 1,3,5(10)-triene.

9. The steroid ether of claim 1 wherein the ether is 1,3-bis(4'methoxytetrahydropyran 4 yloxy) 17ozethynylestra-1,3 ,5 10-trien-17,B-ol.

10. The steroid ether of claim 1 wherein the ether isl,3-bis(4'-methoxytetrahydropyran 4' yloxy)17methnyl-l7fi-acetoxyestra-1,3,5(10)-triene.

11. The steroid ether of claim 1 wherein the ether is 175-(4'methoxytetrahydropyran 4' yloxy) estra- 1,3,5(10)-trien-3-ol.

12. The steroid ether of claim 1 wherein the ether is 26 (4methoxytetrahydropyran-4'-yloxy)-l8-methylestra-1,3,5(10)-trien-3-ol.

13. The steroid ether of claim 1 wherein the ether is3-cyclopentoxy-17fl-(4rnethoxytetrahydropyran 4-yloxy)-estra-1,3,5(10)-triene.

14. The steroid ether of claim 1 wherein the ether is3-cyclopentoxy-17B-(4 methoxytetrahydropyran 4-yloxy)-l8-rnethylestra-l,3,5(10)-triene.

15. The steroid ether of claim 1 wherein the ether is3-acetoxy-17fi-(4-methoxytetahydropyran 4 yloxy)-estra-1,3,5(10)-triene.

16. The steroid ether of claim 1 wherein the ether is3-tetrahydropyran-2-yloxy-17;?-(4'methoxytetrahydropyran-4-yloxy)-estra-1,3,5(10)-triene.

17. The steroid ether of claim 1 wherein the ether is 3-cyclopentoxy17oz ethynyl l7B-(4'-methoxytetrahydr0pyran-4-yloxy -estral ,3 ,5 10-triene.

18. The steroid ether of claim 1 wherein the ether is3-cyclopentoxy-17a-ethynyl-17 8-(4' methoxytetrahydropyran-4'-yloxy) -18methylestra-1,3 ,5 10)-triene.

19. The steroid ether of claim 1 wherein the ether is1,3-diacetoxy-17u-ethynyl-l7fi-(4methoxytetrahydropyran-4'-y1oxy)-estra-l,3,5(10)-triene.

20. The steroid ether of claim 1 wherein the ether is17ot-ethynyl-l7B-(4' methoxytetrahydropyran-4-yloxy)-estra-1,3,5(l0)-triene-3,l6a-diol.

21. The steroid ether of claim 1 wherein the ether is 1715' (4'methoxytetrahydropyran-4'-yloxy)-estral,3,5(10),7-tetraen-3-ol.

References Cited UNITED STATES PATENTS 3,256,273 6/1966 Cross 260-239.553,290,297 12/1966 Cross 260239.55 3,294,786 12/1966 Cross et a1.260-239.55

HENRY A. FRENCH, Primary Examiner US. Cl. X.R.

